Submissions for variant NM_002528.7(NTHL1):c.712G>A (p.Ala238Thr)

gnomAD frequency: 0.00043  dbSNP: rs147559648

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801248	SCV000941019	uncertain significance	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 246 of the NTHL1 protein (p.Ala246Thr). This variant is present in population databases (rs147559648, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 646870). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001026335	SCV001188696	likely benign	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000801248	SCV002015436	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer who also harbored variants in other genes (PMID: 32295625); This variant is associated with the following publications: (PMID: 32295625)
Sema4, Sema4	RCV001026335	SCV002529012	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	curation
Baylor Genetics	RCV003461127	SCV004192076	uncertain significance	Familial adenomatous polyposis 3	2024-02-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000801248	SCV004222223	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	The NTHL1 c.736G>A (p.Ala246Thr) variant has not been reported in individuals with NTHL1-related conditions in the published literature. The frequency of this variant in the general population, 0.0016 (41/24956 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV003461127	SCV005638577	uncertain significance	Familial adenomatous polyposis 3	2024-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928275	SCV004747071	likely benign	NTHL1-related disorder	2024-08-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).